Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITION COMPRISING A TRPA1
ANTAGONIST AND AN ANTICHOLINERGIC AGENT
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent
Application number 3418/MUM/2011 (filed on Dec. 5, 2011), the contents of
which are incorporated by reference herein.
FIELD OF THE INVENTION
The present patent application relates to a pharmaceutical composition
comprising a transient receptor potential ankyrin-1 receptor ("TRPA1")
antagonist
and an anticholinergic agent. Particularly, the application provides a
pharmaceutical composition comprising a TRPA1 antagonist having IC50 for
inhibiting human TRPA1 receptor activity of less than 1 micromolar and an
anticholinergic agent; a process for preparing such composition; and its use
in
treating a respiratory disorder in a subject.
BACKGROUND OF THE INVENTION
Respiratory disorders related to airway inflammation include a number of
severe lung diseases including asthma and chronic obstructive pulmonary
disease
("COPD"). The airways of asthmatic patients are infiltrated by inflammatory
leukocytes, of which the eosinophil is believed to be the most prominent
component. Inflammatory sensitization of airway neurons is believed to
increase
nasal and cough sensitivity, heighten the sense of irritation, and promote
fluid
secretion, airway narrowing, and bronchoconstriction.
TRPA1 receptor activation in the airways by exogenous noxious stimuli,
including cold temperatures (generally, less than about 17 C), pungent natural
compounds (e.g., mustard, cinnamon and garlic), tobacco smoke, tear gas and
environmental irritants as well as by endogenous biochemical mediators
released
during inflammation, is supposed to be one of the mechanisms for neurogenic
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inflammation in the airways. Neurogenic inflammation is an important component
of chronic airway diseases like COPD and asthma.
International Publication Nos. viz., WO 2004/055054, WO 2005/089206,
WO 2007/073505, WO 2008/0949099, WO 2009/089082, WO 2009/002933 WO
2009/158719, WO 2009/144548, WO 2010/004390, WO 2010/109287, WO
2010/109334, WO 2010/109329, WO 2010/109328, WO 2010/125469 and WO
2010/004390 describe various transient receptor potential ("TRP") receptor
modulators.
Anticholinergic agents are believed to inhibit vagally-mediated reflexes by
blocking acetylcholine at the cholinergic receptor. Anticholinergic agents are
also
believed to inhibit secretions of the serous and sero-mucous glands of the
nasal
mucosa. Anticholinergic agents for treatment or control of respiratory
disorders
include tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or
salt
thereof
One known anticholinergic agent is tiotropium bromide, the chemical name
of which is, (1 a, 2B, 4B, 5a, 7B)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-
dimethy1-
3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. Tiotropium
bromide is available commercially as SPIRIVA capsules containing 18 mcg
tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) marketed by
Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. Tiotropium
bromide is indicated for the maintenance treatment of bronchospasm associated
with COPD, and for reducing COPD exacerbations.
Another anticholinergic agent, ipratropium bromide is chemically, 8-
azoniabicyclo (3.2.1) octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methy1-8-
(1-methylethyl)-, bromide monohydrate. Ipratropium bromide is commercially
available as ATROVENTO 0.06% nasal spray (42 mcg per spray) marketed by
Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. It is
administered
as a pressurized metered-dose aerosol unit for oral inhalation. Each actuation
of the
inhaler delivers 21 mcg of ipratropium bromide. Ipratropium bromide is
indicated
for the symptomatic relief of rhinorrhea associated with the common cold or
seasonal allergic rhinitis. ATRO VENT HFA is another product of ipratropium
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bromide is approved as a bronchodilator for maintenance treatment of
bronchospasm associated with chronic obstructive pulmonary disease (COPD),
including chronic bronchitis and emphysema.
Aclidinium bromide, chemically known as [(8R)-1-(3-phenoxypropy1)-1-
azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide
is a
novel long acting inhaled muscarinic antagonist. It is approved as TUDORZAO
PRESSAIR 0.375mg/INH in the United States. It is approved for the long-term
maintenance treatment of bronchospasm associated with chronic obstructive
pulmonary disease (COPD), including chronic bronchitis and emphysema.
Another anticholinergic agent, glycopyrrolate is chemically 3-(2
cyclopenty1-2-hydroxy-2-phenylacetoxy)-1, 1-dimethylpyrrolidinium
trA
4Li
t-\IIAN`r\ire
"--
(Glycopyrrolate)
Glycopyrrolate is being developed for the treatment of asthma and COPD.
There still exists a need for an effective therapeutic treatment for
respiratory disorders like asthma, COPD and rhinorrhea.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising a
TRPA1 antagonist and an anticholinergic agent.
The inventors have surprisingly found that a TRPA1 antagonist and an
anticholinergic agent act synergistically in the treatment of respiratory
disorders
and are more effective and provide better therapeutic value than treatment
with
either active ingredient alone.
The anticholinergic agent, as contemplated herein, including tiotropium,
oxitropium, ipratropium, glycopyrrolate and aclidinium or their salt may be
present
in the form of their stereoisomers, polymorphs, and solvates, including
hydrates,
all of which are included in the scope of the invention.
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In another embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having an IC50 for inhibiting human TRPA1 receptor activity of less than 1
micromolar having structure of formulae: (XII) or (D)
R9 R8 R7 rik o,a,
o s \ 11 Rs 0
R4 R5
H I\IS
Het H
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
group consisting of
o ,
o =
Ra
Ri. R 1,
y--11"---r-S_Ra
I I N 2
5 5 5
R1, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
selected from the group comprising of hydrogen, halogen, cyano, hydroxyl,
nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
and an anticholinergic agent.
In an aspect of the embodiment, the TRPA1 antagonist as contemplated
herein and the anticholinergic agent are present in a weight ratio ranging
from
about 1:0.0001 to about 1:10000.
In yet another embodiment, the present invention relates to a
pharmaceutical composition comprising synergistically effective amount of a
TRPA1 antagonist having structure of formula:
0 S\
0
H3C.N . il "
1
4..r.cu.' ),ii F
F CF3
0 N ¨
CH 3
and an anticholinergic agent.
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In an embodiment, the present invention relates to a method of treating a
respiratory disorder in a subject, said method comprising administering to the
subject the pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1
5 receptor activity of less than 1 micromolar as contemplated herein and an
anticholinergic agent.
The respiratory disorder, in the context of present invention, includes but is
not limited to airway inflammation, asthma, emphysema, bronchitis, COPD,
sinusitis, rhinitis, cough, respiratory depression, reactive airways
dysfunction
syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced
asthma, occupational asthma, sensory hyper-reactivity, multiple chemical
sensitivity, and aid in smoking cessation therapy.
In a further embodiment, the present invention relates to a method of
treating a respiratory disorder in a subject, said method comprising
administering
the subject a pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1
receptor activity of less than 1 micromolar as contemplated herein and an
anticholinergic agent selected from a group consisting of tiotropium,
oxitropium,
ipratropium, glycopyrrolate and aclidinium or salts thereof
In a further embodiment, the present invention relates to use of
synergistically effective amount of a TRPA1 antagonist having an IC50 for
inhibiting human TRPA1 receptor activity of less than 1 micromolar as
contemplated herein and an anticholinergic agent in the preparation of a
pharmaceutical composition of the present invention for the treatment of a
respiratory disorder in a subject.
In a further embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having an IC50 for inhibiting human TRPA1 receptor activity of less than 1
micromolar as contemplated herein and an anticholinergic agent for the
treatment
of a respiratory disorder in a subject.
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In an embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having structure of formula:
o S\
H3c_N ()),L4H F CF3
J, I
0 N S
CH3
and an anticholinergic agent selected from a group consisting of tiotropium,
oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof In an
aspect of this embodiment, the pharmaceutical composition is a fixed dose
combination. In another aspect of the embodiment, the composition is for
inhalation administration.
In yet another aspect of this embodiment, the composition is for inhalation
administration, wherein the TRPA1 antagonist and the anticholinergic agent are
present in a weight ratio from about 1:0.001 to about 1:300.
In an embodiment, the present invention relates to a method of treating a
respiratory disorder in a subject, said method comprising administering to the
subject the pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having structure of formula:
o S\
H3c_N ()),L4NN H
F CF3
J, I
0 N S
CH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating
COPD by reducing neutrophil count in a subject, said method comprising
administering to the subject the pharmaceutical composition comprising
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
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0 S NN =
H3c_N Yi4:H F CF3
I
0 N S
OH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of this
embodiment, the respiratory disorder is asthma. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of reducing
neutrophil count in a subject, said method comprising administering to the
subject
the pharmaceutical composition comprising synergistically effective amount of
a
TRPA1 antagonist having structure of formula:
0 H s \
.N (ANN
H3c
2:)1
F CF3
0 N S
OH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating
asthma by inhibiting airway resistance in a subject, said method comprising
administering to the subject the pharmaceutical composition comprising
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
0S\
H3c.N H N N
FlICF3
0 N S
OH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of this
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embodiment, the respiratory disorder is asthma. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of inhibiting
airway resistance in a subject, said method comprising administering to the
subject
the pharmaceutical composition comprising synergistically effective amount of
a
TRPA1 antagonist having structure of formula:
0 s =
H3c.NYH F CF3
\
0 N S
aH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of the
embodiment, the composition is for inhalation administration.
In another embodiment, the present invention relates to use of
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
0 s
H3c.NYcL,..HNN
F CF3
\
0 N s
aH3
and an anticholinergic agent in the preparation of a pharmaceutical
composition of
the present invention for the treatment of a respiratory disorder in a
subject. In an
aspect of this embodiment, the anticholinergic agent selected from a group
consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and
aclidinium or
salts thereof In another aspect of the embodiment, the composition is for
inhalation administration.
In a further embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having structure of formula:
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0 S NN =
H3c_N Yi4:H F CF3
I
0 N S
aH3
and an anticholinergic agent for the treatment of a respiratory disorder in a
subject.
In an aspect of the embodiment, the composition is for inhalation
administration.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar graph showing the effect of Compound 52, tiotropium
bromide, and their combination on methacholine-induced bronchoconstriction in
male Dunkin Hartley guinea pigs.
Figure 2 is a bar graph showing the effect of Compound 52, aclidinium
bromide, and their combination on LPS induced neutrophilia in male SD rats.
Figure 3 is a bar graph showing the effect of Compound 52, tiotropium and
their combination on LPS induced neutrophilia in female SD rats.
Figure 4 is a bar graph showing the effect of Compound 52, ipratropium
bromide and their combination on LPS induced neutrophilia in male SD rats.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms used herein are defined as follows. If a definition set forth in the
present application and a definition set forth earlier in a provisional
application
from which priority is claimed are in conflict, the definition in the present
application shall control the meaning of the terms.
The term "effective amount" or "therapeutically effective amount" denotes
an amount of an active ingredient that, when administered to a subject for
treating
a respiratory disorder, produces an intended therapeutic benefit in a subject.
The therapeutically effective amount of TRPA1 antagonist as described
herein ranges from about 0.1mcg/kg to about 20mg/kg, and preferably from about
lmcg/kg to about 15mg/kg.
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The therapeutically effective amount tiotropium to be administered per day
ranges from about 5 iLig to about 50 iLig and preferably from about 10 iLig to
about
36 g. Preferably, the discrete dosage strength of tiotropium or its salt is
18 g.
The therapeutically effective amount of ipratropium to be administered per
5 day ranges from about 0.05 mg to about 10 mg, and preferably from about
0.1 mg
to about 1 mg. Preferably, the discrete dosage strengths of ipratropium or its
salt
are 168 iLig or 336 iLig or 504 iLig or 672 g.
The therapeutically effective amount of aclidinium to be administered per
day ranges from about 0.05 mg to about 10 mg, and preferably from about 0.1 mg
10 to about 1 mg. Preferably, the discrete dosage strengths of aclidinium
or its salt are
200 iLig or 400 iLig or 800 g.
The therapeutically effective amount of glycopyrrolate to be administered
per day ranges from about 0.01 mg to about 10 mg, and preferably from about
0.1
mg to about 1 mg.
The therapeutically effective ranges of actives are given as above, although
larger or smaller amount are not excluded if they fall within the scope of the
definition of the above paragraphs.
The term "active ingredient" (used interchangeably with "active" or "active
substance" or "drug") as used herein includes a TRPA1 antagonist, an
anticholinergic agent or a pharmaceutically acceptable salt thereof.
Preferably, the
active ingredient includes TRPA1 antagonist having a human IC50 value of less
than 1 micromolar, tiotropium, oxitropium, ipratropium, glycopyrrolate and
aclidinium or its salt.
The IC50 value is believed to be measure of the effectiveness of a
compound in inhibiting biological or biochemical function. This quantitative
measure generally indicates molar concentration of a particular compound (or
substance) is needed to inhibit a given biological process by half In other
words, it
is the half maximal (50%) inhibitory concentration (IC) of the compound. The
IC50
of a drug compound (or active substance) can be determined by constructing a
concentration-response curve so as to examine the effect of different
concentrations of antagonist on reversing agonist activity. IC50 values can be
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calculated for a given antagonist by determining the concentration needed to
inhibit half of the maximum biological response of the agonist. IC50 values
can be
used to compare the potency of two antagonists.
By "salt" or "pharmaceutically acceptable salt", it is meant those salts and
esters which are, within the scope of sound medical judgment, suitable for use
in
contact with the tissues of humans and lower animals without undue toxicity,
irritation, and allergic response, commensurate with a reasonable benefit to
risk
ratio, and effective for their intended use. Representative acid additions
salts
include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate,
oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate,
phosphate,
tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate,
ascorbate,
glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali
or
alkaline earth metal salts include the sodium, calcium, potassium and
magnesium
salts.
The term "treating" or "treatment" as used herein also covers the
prophylaxis, mitigation, prevention, amelioration, or suppression of a
disorder
modulated by the TRPA1 receptor, or the anticholinergic agent, or by a
combination of the two in a subject.
The respiratory disorder includes but is not limited to airway inflammation,
asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory
depression, reactive airways dysfunction syndrome (RADS), acute respiratory
distress syndrome (ARDS), irritant induced asthma, occupational asthma,
sensory
hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation
therapy. Preferably, the respiratory disorder is asthma or COPD.
The term "subject" includes mammals like human and other animals, such
as domestic animals (e.g., household pets including cats and dogs) and non-
domestic animals (such as wildlife). Preferably, the subject is a human.
By "pharmaceutically acceptable excipients", it is meant any of the
components of a pharmaceutical composition other than the actives and which
are
approved by regulatory authorities or are generally regarded as safe for human
or
animal use.
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The term "synergistic" or "synergy", as used herein, refers to a combination
exhibiting an effect greater than would be expected from the sum of the
effects of
the individual components of the combination alone. The term "synergistic" or
"synergy" with regard to the combination of a TRPA1 antagonist with an
anticholinergic agent which is used in the treatment of a respiratory disorder
(for
example, in the form of a pharmaceutical composition, a combination product or
a
kit according to the invention) refers to an efficacy for the treatment of the
respiratory disorder that is greater than would be expected from the sum of
their
individuals effects. The advantages for the synergistic combinations of the
present
invention include, but are not limited to, lowering the required dose of one
or more
of the active compounds of the combination, reducing the side effects of one
or
more of the active compounds of the combination and/or rendering one or more
of
the active compounds more tolerable to the subject in need of treatment of the
respiratory disorder.
Combinations
The present invention relates to a pharmaceutical composition comprising a
TRPA1 antagonist and an anticholinergic agent.
The inventors have surprisingly found that a TRPA1 antagonist and an
anticholinergic agent act synergistically in the treatment of respiratory
disorders,
and are more effective and provide better therapeutic value than treatment
with
either active ingredient alone.
In an aspect, TRPA1 antagonists useful in the context of the invention, are
selected from one of the following formulae: (A) or (B) or (C) or (D)
R9 R8 R7 R9 R8 R7 railli 0,..õ0,
N _OH 0
0 si: Ik R6 0 r . R6
AN/ N Y
, F 0 5 400 y1-I
I
R4 R5 N p R4 R5 NS-
(A) (B) (C) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
group consisting of
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0 , o _ o , o , o ,
iRi )Ai Ri, Rl.NAI R1-.N R1 )-____Al
N '11 1
i 1 0 t,i j......._;N
Ni!--N N 0 N 0 N ONN 0 N
\¨/ i 2
R i
R2 i 2
R i
R2
5 5 5 5
0
FilN)H_ pql
R1, I \ Ra ' ' 1\11 )Yµ Ri Ri
11 'I\I N
y-i---_Ra i N
.--'0 ----- 1
(i)N."---S ON 0 N S 0 N N 0 N
I I,
R2 R2 Ft- R2 R2
5 5 5 5 5
0 ,
0 ,
RI.N)0 , N1, R1N1
,..õAl R1 i 1.-S¨C1
I 0
IONI\i/ IONIO
0 N N
R12 I , i
Ft- R2
5 5 ;
P is selected from
RC 0
\./(:).(Rb
0 1 o_p11,0R1
, \/ NH2 \OR10
5 0 ;
R1, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
Rb and Rc independently selected from hydrogen, substituted or
unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from the group comprising of hydrogen, halogen, cyano,
hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl;
Rm is selected from hydrogen, alkyl, arylalkyl and pharmaceutically
acceptable cation.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in
W02009144548. Accordingly, a TRPA1 antagonist useful in the context of the
invention has the formula (I):
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R7
0
R6
N N
H3C, J\T
N
H
NN N
(I)
or a pharmaceutically acceptable salt thereof,
wherein,
R6 represents hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
substituted
or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted
or
unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
or
unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring
and
substituted or unsubstituted heterocyclylalkyl;
R7 independentlyrepresents hydrogen or alkyl.
Few representative TRPA1 antagonists useful in the methods of the
invention are mentioned below:
0
0 r4 0
0 N 1.1
NN-1--N N FIN-4
r( N H3C=NN N¨t
H S
N
N N N
Br L--/
Compound 1 Compound 2
The preparation of above said compounds is described in W02009144548.
In another aspect, TRPA1 antagonists useful in the context of the invention
are selected from those compounds generically or specifically disclosed in
W02010004390. Accordingly, TRPA1 antagonist useful in the context of the
invention has the formula (II):
0 0 (R6
0
N
R2
(II)
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or pharmaceutically acceptable salts thereof,
wherein,
at each occurrence Wand R2 is independently selected from hydrogen,
5 hydroxyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, (CRxRY)õ0Rx, CORx, COORx,
CONRxRY, SO2NRxR3J, NRxRY, NRx(CRxRY)õ0Rx, NRx(CRxRY)õCN (CH2)õNRxR3J
,
(CH2)õCHRxR3J, (CRxRY)NRxRY, NRx(CRxRY)õCONRxRY, (CH2)õNHCORx and
10 (CH2)õNH(CH2)õSO2R1', (CH2)õNHSO2Rx;
Rx and RY are independently selected from hydrogen, hydroxyl, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted
or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted
or
unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
15 substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted
or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted
or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl;
Rx and RY may be joined together to form an optionally substituted 3 to 7
membered saturated, unsaturated or partially saturated cyclic ring, which may
optionally include at least two heteroatoms selected from 0, NRaor S;
ring A is selected from phenyl, pyridinyl, pyrazolyl, thiazolyl and
thiadiazolyl;
each occurrence of R6 is independently hydrogen, cyano, nitro, -NRxRY,
halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted
or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted
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or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl,
Rx and RY are independently selected from hydrogen, hydroxyl, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted
aryl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, and
substituted or unsubstituted heteroarylalkyl;
at each occurrence of 'n' is independently selected from 1 to 5.
According to one aspect, specifically provided are compounds of the
formula (Ha)
R6b
0
N N
1 0 H
R
T 0
0 N
I 2
R
(Ha)
or pharmaceutically acceptable salts thereof,
wherein,
Rl and R2 are as defined above for the compound of formula (II);
R6a and R6b are independently selected from hydrogen, cyano, nitro, -
NRxRY, halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted
or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted
or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted
or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl, -C(0)0R1', -0Rx, -C(0)NRxRY, -C(0)R1', -SO2Rx, -S02-NRxRY.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
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17
O S\ * 0 S \ .
CI
NN Br
NN
0 0
H3C, H H3C, H CI
N 6 N 0
Cf' N O'N
I i
CH3 CH3
Compound 3 Compound 4
.
0 S\ 0 S\
NN .
.6. I
0 0 N ,iN CH3
H3C, H H3C, H
N 6 N 6
Cf' N ON
i I
CH3 CH3
Compound 5 Compound 6
0 S\ .
N):,- 0 N 0 N\r
0 n *
01
l
H30, H CF3 H30, H
N 6
6
C:t N
ON
I I
CH3 cH3
Compound 7 Compound 8
O S\ .
N .1-,:=N
CI H3C, o
0 0 \ . .
H30..6
H N'''1\1
N
;N 40 H
Ct' N ..
I I
CH3 CH3
Compound 9 Compound 10
0 C F3 );., S \ . 0 S \ *
C(CH3)3
0 N N 0 N N
H3C, H H3C, H
;N 40
I I
cH3 cH3
Compound 11 Compound 12
0 S\ . F 0 s \ .
CH(CH3)2
NN 1._
0 0 N --1\I
H3C,
0 N H F H3C N 40 , H
I I
cH3 cH3
Compound 13 Compound 14
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18
0 S \ *
F N
0 N 0 N N
H3C, H CI HC H C F3
11 *
0 N 1 0
0 N
I I
CH3 CH3
Compound 15 Compound 16
0 s \ 4. 0 s \ *
C F3
A.
0 N N CH3 0 N N
H3C, H H3C, H F
11
0 0 0
0 Ij (40
N N
I I
CH3 cH3
Compound 17 Compound 18
0 N N * 0 s \ . C F3
0 N AN F
H3C, H F H3C, H C F3
1 0
0 N \l, 0
0 N
I 1
cH3 cH3
Compound 19 Compound 20
o 1 \ if
a o I \ .. 0
0 N N 0 N N
H3C,, H CF3 H3C, H \--¨ CH3
IN 1. ON
CH3
0 HC
O
I I
CH3 CH3
Compound 21 Compound 22
ci
0 s \
0 N * 0 s \ *
N .6.: ...1:-.
CH3 0 N N
H3C, H H30 H3C, H F
\l, 0
\l, 0
ON ON
I
CH3 6H3
Compound 23 Compound 24
0 S\ * 0 S\ *
r, 0 N N 0 N N
H3v, H F CI H3 Cs H OC F3
1 0
0 N0 ;1 a
N -glir
61-13 61-I 3
Compound 25 Compound 26
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19
0 S\ 0 S
CF 3
0 N N 0 N N
H3C, F F H3's F F
= 0 N ON
61-13 61-13
Compound 27 Compound 28
0 S
= OC F3 0 NN . 0cH F2
0 N N H3C,
H3 CI
L,
-y
0
ON1 N
61-13 CH3
Compound 29 Compound 30
0 S 0 S
NN
0
0 0 N N "¨ CF3
H3C, H F CF3 H3C,
ON 0 N
a-13 a-13
Compound 31 Compound 32
Os
0 N N CF3
H3C,
ON
CH3
Compound 33
The preparation of above said compounds is described in W02010004390.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in
W02010109287. Accordingly, TRPA1 antagonist useful in the context of the
invention has the formula (III):
0 L N¨U¨V
R1 õ,K__.)3 F13
Z2
0 N Zi
I ,
(III)
or a pharmaceutically acceptable salt thereof,
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wherein,
Z1 is NRa or CRa;
Z2 is NRb or CRb;
Z3 is N or C;
5 with the proviso that when Z2 is CRb then both Z1 and Z3 are not
nitrogen at
the same time;
at each occurrence, Ra and Rb which may be same or different, are
independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or
unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
10 -(CRxR3J)õ0Rx, -CORx, -COORx, -CONRxRY, -S(0)õ,NRxR3J, -NRxRY,
-NRx(CRxR3J)õ0Rx, -(CH2)õNRxRY, -(CH2)õCHRxR3J, -(CH2)NRxR3J
,
-NRx(CRxRY)õCONRxRY, -(CH2)õNHCORx, -(CH2)õNH(CH2)õSO2Rx and
(CH2)õNHSO2Rx;
alternatively either of Ra or Rip is absent;
15 Rl and R2, which may be same or different, are independently selected
from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl,
alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CRxRY)õ0Rx, CORx, COORx,
CONRxRY, (CH2)õNRxR3J, (CH2)õCHRxR3J, (CH2)NRxR3J and (CH2)õNHCORx;
R3 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl,
20 haloalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
L is a linker selected from -(CRxRY)õ-, -0-(CR1'R31)õ-, -C(0)-, -NRx-, -
S(0)mNRx-, -NRx(CRxRY)õ- and -S(0)õ,NR1'(CR1'R31),i;
U is selected from substituted or unsubstituted aryl, substituted or
unsubstituted five membered heterocycles selected from the group consisting of
thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole,
imidazole, furan, thiophene, pyroles, 1,2,3-triazoles and 1,2,4-triazole; and
substituted or unsubstituted six membered heterocycles selected from the group
consisting of pyrimidine, pyridine and pyridazine;
V is selected from hydrogen, cyano, nitro, -NRxRY, halogen, hydroxyl,
substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl,
cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
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21
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -
C(0)0Rx, -
0Rx, -C(0)NRxR3I, -C(0)Rx and -SO2NRxR3I; or U and V together may form an
optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring,
that
may optionally include one or more heteroatoms selected from 0, S and N;
at each occurrence, Rx and RY are independently selected from the group
consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and
at each occurrence 'm' and 'n' are independently selected from 0 to 2, both
inclusive.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
CI
0 S \ 0 S
0 \
OCH2CH2CF3
3
N N = 0 C F 0 ?L N
H3C-.= H H3C.N )cjc) H CI
0 N 0 N
6H 3 CH3
Compound 34 Compound 35
0 S 0 S
o
O
CF3 0 N C H2C F3
N
H3C.N Af.) H H3C;I. Li N H
I /ON,
0 N
CH3 CH3
Compound 36 Compound 37
0 s 0 s
NN &NN cF3 cF3
H3c.N f'-' y- H F H3C.N H
0N1 N
A J\J -CH3 A õ - CH 3
- N
6-13 61-13
Compound 38 Compound 39
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22
F
0 S \ *
0 (NNOCH2C(CH3)3 I. \ o . OCF3
I
H3C,NAxi\i, H F H3CN
. 11 N F ,N --
i ,N-CH3
ON ON N
OH3 CH3
Compound 40 Compound 41
ci F
Jk
0 S \ * J. OCH2C(CH3)3 0 S \ * 0
k ,L,
o r N N o (NN
H3C, .11,1 H F H3C,,,,..Are, H F
N
0 N O¨N
i I
CH3 CH3
Compound 42 Compound 43
a 0 s \
t \
=
0 r\l N * OCH2(3)3 n(NNC CH 0 "N w 00H20(0H3)3
õ k' H 1
n3,õIL
s. L: H CI ..3 - , jilt; H
N F I "'N 1 lv
0 N 0 N
i I
CH3 CH3
Compound 44 Compound 45
The preparation of above said compounds is described in W02010109287.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in WO
2010109334. Accordingly, TRPA1 antagonists useful in the context of the
invention has the formula (IV)
R9 R8 R7
)o
S \ . R6
N
0 N R4 R5
H
Rl.
NA-1.)_Ra
----q
0 N ¨
1,
IR'
(IV)
or a pharmaceutically-acceptable salt thereof.
wherein, Rl, R2 and Ra, which may be the same or different, are each
independently hydrogen or (C1-C4)alkyl;
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23
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from the group comprising of hydrogen, halogen, cyano,
hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
\ A
CF3 a
j., I
y, c.,(N-k--N IN VN-6N
H3c.N , H F H3C.,, H CI ` CH (CH3)2
0 N S 0 N S
aH3 aH3
Compound 46 Compound 47
F F
OCH F2 0 S \ =
OCH2CF3
VIV6N yi_e(LN't*:='N
H3C,õ, H F H3C,õ, H F
IN 1 \ IN \
I CH2CH3 I CH2CH3
0 N S 0 N S
01-13 CH3
Compound 48 Compound 49
0 s \
4
0 N)=---N
. CF3 0 0 S \ 1
m .6..m CF3
,
H3c.N H3CN H . -
1cL..... H F F
\
\ CH2CH3 I
0 N S ON S
a H3 aH 3
Compound 50 Compound 51
jc...
0 S\
0 * F
(NN
H3C;.,, J H F CF3
,' I \
0 N s
CH3
Compound 52
The preparation of above said compounds is described in W02010109334.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in
W02010109329. Accordingly, TRPA1 antagonists useful in the context of the
invention has the formula (V)
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24
R9 R8 R7
ji) S\ . R8
0 ..===).4---N "--- N
R4 R5
R1., , --lip_ H
j, I \ Ra
0 N 0
1 2
R
(V)
or a pharmaceutically acceptable salt thereof,
wherein, Rl, R2 and Ra which may be the same or different, are each
independently
hydrogen or (Ci-C4) alkyl; and
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from the group comprising of hydrogen, halogen, cyano,
hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
F
OCH2CH(CH3)2
CF3
H3C
jocr( H F H3CNA-N VN A-N
, H F
,N \ N \
I I
0 N 0 0 N 0
61-13 CH3
Compound 53 Compound 54
CF3 F
Vr\J'N yLNA'N ocH2cF3
H3C,N H F H3 C-N H F
\ \
I I
0 N 0 0 N 0
61-13 CH3
Compound 55 Compound 56
ci
0 s \
ocH2cF3 0 s \ .
F
H3c
VN)z-s.N 40, D ...pN H CI H3C,i H
CF3
N \ N \
II
0 N0 0 NO
61-13 CH3
Compound 57 Compound 58
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CI
N
ocH2cF3
y....._.LN-6N (j)'61\1
H3C, H F
H3C,N \ H F kA õ -3 N \
1 j.... I
0 N 0
61-13 CH3
Compound 59 Compound 60
CF3 F
ocH2cF3
ii)N-6N
VNA-N
H3CN F H3CN
, H F
, \ H
\
ON 0
61-13 CH3
Compound 61 Compound 62
0 S\ A
a
0 S\
A.41 F
y(jc__NN 0 N N
H3C, H OC F3 H3C-N H F CF3
N
=)-- I \ CH3 I \ CH3
ON 0 0 N 0
5 CH3 OH3
Compound 63 Compound 64
F
0 S\
NN . 0 NN \ .
CF3 ocH2c(cH3)3
c)(L....'
H3CN, H F H3C, H N \
CH3 F
0..A'N I 0\ ON 0
61-13 61-13
Compound 65 Compound 66
0 S\ 0 0 s \ 40
.A...
,õ H3c VHN.A-N ocFF3
H3c, m m k' -
N . ..., 3 -N ,
CH3 I ' CH3
0..A'N I (:' 0 N 0
61-13 61-13
10 Compound 67 Compound 68
H3C 0 s \ .
F 0 S \ A
OCF3
N p C
CF3 lyci.....6N
, HN H3 H F
N \ VI 3
0 N 0 0 N 0
61-13 61-13
Compound 69 Compound 70
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26
0 S
* CI 0 S =
CF3
H3CN, õ-3 H H3C, H
n CH3 kA N
A CH3
N =-= 0' N 0
aH3 CH3
Compound 71 Compound 72
0 s 40,
"A
NN
OC F3 N
0 S
OC H2CF3
H3C, H CI H3C, H CI
N N
A I CH3 A I CH3
0-''N 0 0"-N 0
aH3 aH3
Compound 73 Compound 74
ci F F
0 cF3 S
OCH2CH(0H3)2 0 S
H3C, H CI H3C, H
N N
,L [-CH I CH3
0' N 0 N 0
CH3 CH3
Compound 75 Compound 76
The preparation of above said compounds is described in W02010109329.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in
W02010109328. Accordingly, TRPA1 antagonists useful in the context of the
invention has the formula (VI)
R9 R8 R7
0 S\ 441
R6
0 )N
R4 R5
I N
CDN
R2
(VI),
or a pharmaceutically-acceptable salt thereof.
wherein, Rl and R2, which may be the same or different, are each independently
hydrogen or (Ci-C4)alkyl; and
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from the group comprising of hydrogen, halogen, cyano,
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hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
N 'It:N *
ci....\C.NO N F 'N 0 CF3
H3C.N H F CF3 H3C.N \ H F
I
5N
0 N 5 0 N
aH3 aH3
Compound 77 Compound 78
H3c.N o 0IFIIN\ 0 s \
I 1\1
Jcrek 0
" li
FlICF3 H3C.N HA
_i_ I N a 0CF3
0-'1\1 5 CY-N 5
aH3 aH3
Compound 79 Compound 80
0 s \ = 0 s \ *
CF3
yykN-k---N 0 N N 00 F3
H3C,N H F H3CNL H F
=
I 1\1 I 1\1
ON 5 ONS
aH3 aH3
Compound 81 Compound 82
CF3
Os
* Os
O \
H3c.NJ A.,.....e N L F H 0 N N
3C.N \ h1) * CF3
F F
CY-N S 0 N 5
C1-13 CH3
Compound 83 Compound 84
The preparation of above said compounds is described in W02010109328.
In one aspect, TRPA1 antagonists useful in the context of the invention are
selected from those compounds generically or specifically disclosed in
W02010125469. Accordingly, TRPA1 antagonists useful in the context of the
invention have the formulas (VIIa, VIIb and VIIc):
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28
0 0 NH¨U-0
(Rz) H3 CNN
I I
0-"¨N N Ra Ra p
CH3 CH3 Ra
(Vila) (VIIb)
0 NH¨U-0
\ /
H3C,NN
( Rz)p
;)
0 N N Ra
CH3
(Vile)
or pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, Ra is selected from hydrogen, cyano, halogen,
substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl
and cycloalkylalkyl;
U is substituted or unsubstituted five membered heterocycle, for example
selected from the group consisting of
Rb Rb
N ¨0
and
R =
at each occurrence, Rb is independently selected from hydrogen, halogen,
cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy,
haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl;
at each occurrence, Rz is independently selected from halogen, cyano,
hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring,
heterocyclylalkyl,
COORx, CONRxRY, S(0)õ,NRxRY, NRx(CRxRY)õ0Rx, (CH2)õ1\1RxRY,
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29
NRx(CRxRY)õCONRxRY, (CH2)õNHCORx, (CH2)õNH(CH2)õSO2Rx and
(CH2)õNHSO2Rx;
at each occurrence, Rx andRYare independently selected from hydrogen,
hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl,
cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclic ring and heterocyclylalkyl;
at each occurrence, 'm' and 'n' are independently selected from 0 to 2, both
inclusive; and `p' is independently selected from 0 to 5, both inclusive.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
F F
0 S \
N)
. 0 S \
. OCH2C F3
,=
H3C-N o H N C F3 H3C. o (ANN H F
N
I , I
0 N N, ONN
OH3 OH3
Compound 85 Compound 86
o s \ 0 S \
N .6. N * OC F3
:)1' N 'IN * F
H C. H F CF3 H C o H F
3 N 1 3 -N N
0N ' N
0N
OH3 oH3
Compound 87 Compound 88
The preparation of above said compounds is described in W02010125469.
In one aspect, the TRPA1 antagonist useful in the context of the invention
is Compound 89:
N OH
0
F
Compound 89
In one embodiment, the TRPA1 antagonist useful in the context of the
invention is Compound 90:
o
406 NH
N's
H
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Compound 90
In an embodiment, TRPA1 antagonists useful in the context of the
invention has the formula
R8 R7
o s \ =
N
R6
It o )---N
R4 R5
R1---NA.....--N H
1
0 N N
i,
1=1-
5 (VIII)
or a pharmaceutically-acceptable salt thereof
wherein,
Rl, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4)alkyl;
10 R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
selected from the group comprising of hydrogen, halogen, cyano, hydroxyl,
nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
15 A representative TRPA1 antagonist useful in the context of the invention
is
Compound 91:
0 s \ ao,
Br
0 1\1N
H3C.NAxN H
ON - e
61-13
Compound 91
The Compound 91 may be prepared, for example, by following the process
20 provided for the preparation of similar compounds in PCT publication No.
W02007073505.
In another aspect, TRPA1 antagonists useful in the context of the invention
are selected from those compounds generically or specifically disclosed in
W02011114184. Accordingly, a TRPA1 antagonist useful in the context of the
25 invention has the formula (IX):
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31
R5
0 S \
(R6),
0 N N
R2
(IX)
or a pharmaceutically-acceptable salt thereof
wherein at each occurrence, Rl and R2 are independently selected from
hydrogen or substituted or unsubstituted alkyl;
at each occurrence, R5 is selected from hydrogen, halogen or substituted or
unsubstituted alkyl;
at each occurrence, R6 is selected from hydrogen, cyano, nitro, halogen,
hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
A representative TRPA1 antagonist useful in the methods of the invention
is mentioned below:
o S\
H3C.N H F CF3
ON N
CH3
Compound 92
The preparation of above said compounds is described in W02011114184.
In another aspect, TRPA1 antagonist useful in the context of the invention
has the formula (X):
R9 R8 R7
0 S *
R6
rAN."---11 5
p R4 R5
Het
(X)
wherein, 'Het' is selected from groups consisting of
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32
o , o _ o , o , o ,
iRi )_.,, Ai Ri, Ri.N Al R1-.N R1 )-_____
AI
N '11 1
1 0 ? )......_;N
NNN ON 0 N ONN 0 N
\--I 12
R I
R2 12
R I
R2
5 5 5 5
0
. )H_
R1, I \ Ra . R .11\1 1 )Yµ Ri'll
Ri'll N
y-i---_Ra RlN N
0 N .--' 0 --=---- 1
(i)N..."--S 0 N S 0 N N 0 N
R2 R2 IR' R2 R2
5 5 5 5 5
0 ,
0 ,
0 , R 1 A 7 R1
R1 N
' )-1 . ' y - - -- - - - \,
I
0 N N ON.."'----N (:) N ----' 0
RI2 I , I
IR' R2 =
5 5 5
P is selected from
RC 0 Rb R 0
y oyNH2 /o_pii,oRl
o , \/ \oRl
5 0
R1, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from the group comprising of hydrogen, halogen, cyano,
hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,
arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl;
Rb and Rc independently selected from hydrogen, substituted or
unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
Rm is selected from hydrogen, alkyl, arylalkyl and pharmaceutically
acceptable cation.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
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0 1..
33 0 S
0 S \
0 N-.N
JL.... * OCF3
NH2 H3C,õ,)i_4; F
CI
IN \ 0 F CF3
H3C.N
0 N 0 0 I
0 N S- 15.(OH
6H3
H3C CH3 aH3 - OH
Compound 95 Compound 96
0 S\ . F
H3C. o NN F CF3
VI\l'N
N \ 0 @
I
)ci....-
e o s \
H3c. L. * ocF3
n a
?..1...NH3c1 N
I \ CH3 si'
0 N S
0N 0 C)
CH3
H3C CH3 6H3 NH2.HCI
Compound 97 Compound 98
In another aspect, TRPA1 antagonists useful in the context of the invention
are selected from those compounds generically or specifically disclosed in
W02011114184. Accordingly, TRPA1 antagonist useful in the context of the
invention has the formula (XI):
Rb R8 R7
R
H R4 R5
Ri.
0.'" 'N 0
1 2
R
(XI)
or a pharmaceutically acceptable salt thereof,
wherein, Rl, and R2 are independently hydrogen or (Ci-C4)alkyl; and
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently selected from halogen haloalkyl, dialkylamino, and haloalkoxy.
Few representative TRPA1 antagonists useful in the context of the
invention are mentioned below:
CF3
0 S\ . ,,,E, 0 S \ .
VNA-N L,1 3
yN-'..-N
H3C. H F H3C, H F
I
N \ N I \ CI Cl
0 N 0 0N 0
6-13 61-13
Compound 99 Compound 100
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F CF3
V
H3C,
F H3C, 0 S \ *
00 F3 Nr6N ycx...N1
H H F
N \
N I \ CI
I CI
0 N 0 0 N ¨n
al-13 OH3
Compound 101 Compound 102
F F
1:) 0 S \ .
F 0 S \ 40
CF3
VNA-N
H3C, I H 00 F3 H3C, H I \ CI
ON 0 0 N 0
OH 3 aH3
Compound 103 Compound 104
The preparation of above said compounds is described in W02011114184.
In an aspect, TRPA1 antagonists useful in the context of the invention, is
selected from one of the following formulae: (XII) or (D)
R9 R8 R7
(:)L
S .
R6 0
H R4 R5 400 y H
NS
Het H
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
group consisting of
0
R a R1,.... N. jtx\j,:õ
R1,....N.).õ.........
I N 0
I Ra
0 N S
R2 R2 IR- IR-
Rl, R2 and Ra, which may be the same or different, are each independently
hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
selected from the group comprising of hydrogen, halogen, cyano, hydroxyl,
nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
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Few representative TRPA1 antagonists of the formula (XII) useful in the
context of the invention are compound 52, compound 73 and compound 84 as
described above.
The anticholinergic agent, as contemplated herein, includes tiotropium,
5 oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof
The salt
may be present in the form of their isomers, polymorphs, and solvates,
including
hydrates, all of which are included in the scope of the invention.
In another embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
10 having an IC50 for inhibiting human TRPA1 receptor activity of less than
1
micromolar having structure of formulae: (XII) or (D)
R9 R8 R7
0 S \
R6
H
R4 R5 N
Het
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
15 group consisting of
0 , o , o ,
o a
N R , N I R N p
0 N
1,
5 5 5
R1, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
20 selected from the group comprising of hydrogen, halogen, cyano,
hydroxyl, nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
and an anticholinergic agent. Preferably, the TRPA1 antagonist of the present
25 invention has an IC50 for inhibiting human TRPA1 receptor activity of
less than
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500 nanomolar, or more preferably less than 250 nanomolar, as measured by a
method described herein.
In yet another embodiment, the present invention relates to a
pharmaceutical composition comprising synergistically effective amount of a
TRPA1 antagonist having structure of formula:
0 s =
H3c.NYcL.,('H F CF3
I
0 N S
aH3
and an anticholinergic agent.
In another embodiment, there is provided a pharmaceutical composition
comprising synergistically effective amount of a TRPA1 antagonist as
contemplated herein and an anticholinergic agent in a weight ratio ranging
from
about 1:0.0001 to about 1:10000.
In an embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having structure of formula:
0 s
H3c.N (ANN
!1 H
FIPCF3
0 N S
aH3
and an anticholinergic agent selected from a group consisting of tiotropium,
oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof In
first
aspect of this embodiment, the anticholinergic agent is tiotropium. In second
aspect
of this embodiment, the anticholinergic agent is ipratropium. In third aspect
of this
embodiment, the anticholinergic agent is aclidinium. In another aspect of this
embodiment, the pharmaceutical composition is a fixed dose combination.
The pharmaceutical composition of the present invention may be
administered orally, nasally, intra-tracheally, parenterally, transdermally,
transmucosal, inhalation or by any other route that a physician or a health-
care
provider may determine to be appropriate. Preferably, the route of
administration is
oral or by inhalation.
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In yet another aspect of this embodiment, the composition is for inhalation
administration and the TRPA1 antagonist and the anticholinergic agent are
present
in a weight ratio from about 1:0.001 to about 1:300.
As contemplated herein, the active ingredients may be administered
In a preferred embodiment, both the active ingredients i.e., TRPA1
antagonist and the anticholinergic agent are formulated as a pharmaceutical
composition suitable for administration by the same route (e.g., both the
actives by
oral or inhalation route), or by different routes (e.g., one active by oral
and the
other active by inhalation route).
The pharmaceutical compositions for oral administration may be in
conventional forms, for example, tablets, capsules, granules (synonymously,
"beads" or "particles" or "pellets"), suspensions, emulsions, powders, dry
syrups,
and the like. The capsules may contain granule/pellet/particle/mini-
tablets/mini-
capsules containing the active ingredients. The amount of the active agent
that may
The pharmaceutical compositions for parenteral administration include but
are not limited to solutions/suspension/emulsion for intravenous, subcutaneous
or
intramuscular injection/infusion, and implants. The pharmaceutical
compositions
As set forth above, the pharmaceutical composition includes at least one
pharmaceutically acceptable excipient, which includes but is not limited to
one or
more of the following; diluents, glidants and lubricants, preservatives,
buffering
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In an embodiment, the present invention provides a process for the
preparing a pharmaceutical composition comprising TRPA1 antagonist and an
anticholinergic agent and a pharmaceutically acceptable excipient, wherein the
composition is in the form of a fixed dose combination formulation. The
process
comprises admixing TRPA1 antagonist with the anticholinergic agent.
Alternately,
the process comprises formulating TRPA1 antagonist and the anticholinergic
agent
in such a way that they are not in intimate contact with each other.
In another embodiment, the invention relates to a process for preparing a
pharmaceutical composition comprising TRPA1 antagonist, an anticholinergic
agent and a pharmaceutically acceptable excipient, wherein the composition is
in
the form of kit comprising separate formulations of TRPA1 antagonist and the
anticholinergic agent.
The process for making the pharmaceutical composition may for example
include, (1) granulating either or both the active ingredients, combined or
separately, along with pharmaceutically acceptable carriers so as to obtain
granulate, and (2) converting the granulate into suitable dosage forms for
oral
administration. The typical processes involved in the preparation of the
pharmaceutical combinations include various unit operations such as mixing,
sifting, solubilizing, dispersing, granulating, lubricating, compressing,
coating, and
the like. These processes, as contemplated by a person skilled in the
formulation
art, have been incorporated herein for preparing the pharmaceutical
composition of
the present invention.
Methods of treatment
Asthma and COPD are major chronic diseases related to airway
obstruction. The Global Initiative for Chronic Obstructive Lung Disease
provides
guidelines for the distinction between asthma and COPD. Asthma is believed to
be
a chronic inflammatory disease wherein the airflow limitation is more or less
reversible while it is more or less irreversible in case of COPD. Asthma among
other things is believed to be triggered by inhalation of sensitizing agents
(like
allergens) unlike noxious agents (like particles and certain gases) in case of
COPD.
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Though both are believed to have an inflammatory component, the inflammation
in
asthma is believed to be mostly eosinophilic and CD-4 driven, while it is
believed
to be mostly neutrophilic and CD-8 driven in COPD.
Asthma is clinically classified according to the frequency of symptoms,
forced expiratory volume in 1 second (FE-Vi), peak expiratory flow rate and
severity (e.g., acute, intermittent, mild persistent, moderate persistent, and
severe
persistent) Asthma may also be classified as allergic (extrinsic) or non-
allergic
(intrinsic), based on whether symptoms are precipitated by allergens or not.
Asthma can also be categorized according to following types viz., nocturnal
asthma, bronchial asthma, exercise induced asthma, occupational asthma,
seasonal
asthma, silent asthma, and cough variant asthma.
COPD, also known as chronic obstructive lung disease (COLD), chronic
obstructive airway disease (COAD), or chronic obstructive respiratory disease
(CORD), is believed to be the co-occurrence of chronic bronchitis
(characterized
by a long-term cough with mucus) and emphysema (characterized by destruction
of the lungs over time), a pair of commonly co-existing diseases of the lungs
in
which the airways become narrowed. This leads to a limitation of the flow of
air to
and from the lungs, causing shortness of breath. An acute exacerbation of COPD
is
a sudden worsening of COPD symptoms (shortness of breath, quantity and color
of
phlegm) that typically lasts for several days and is believed to be triggered
by an
infection with bacteria or viruses or by environmental pollutants. Based on
the
FEV1 values, COPD can be classified as mild, moderate, severe and very severe.
It is believed that reduction of eosinophil or neutrophil count and increase
in
FEV1 are important components of the treatment of respiratory disorders such
as
asthma and COPD. It is also believed that there exits an inverse correlation
between
eosinophil or neutrophil count and FEV1 value in human. For example, Ulrik CS,
1995 (Peripheral eosinophil counts as a marker of disease activity in
intrinsic and
extrinsic asthma; Clinical and Experimental Allergy; 1995, Volume 25, pages
820-
827) discloses the relationship between eosinophil count and severity of
asthmatic
symptoms. It describes that in childhood and adulthood subjects, there exists
an
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inverse correlation between number of eosinophils and FEV1% (r = -0.75, P <
0.001, and r = -0.80, P < 0.001, respectively).
Further, Peleman RA, 1999 (The cellular composition of induced sputum in
chronic obstructive pulmonary disease; European Respiratory Journal; 1999,
5 Volume 13, pages 839-843) discloses the relationship between percentage
of
neutrophils and FEV1 in patients with COPD. It describes that in patients with
COPD, an inverse correlation was noted between percentage of neutrophils and
FEV1 (r= -0.48, p < 0.05).
Various classes of drugs are currently being used for the treatment and/or
10 prophylaxis of respiratory disorders like asthma and COPD. Some of the
classes of
such drugs are leukotriene receptor antagonists, antihistamines, beta-2
agonists,
anticholinergic agents and corticosteroids.
Human airways are innervated by a generous supply of efferent,
cholinergic, parasympathetic autonomic nerves. Motor nerves derived from the
15 vagus form ganglia within and around the walls of the airways. Release
of
acetylcholine (ACh) at these sites results in stimulation of muscarinic
receptors and
subsequent airway smooth muscle contraction and release of secretions from the
submucosal airway glands. Epithelial and inflammatory cells also generate ACh
and express functional muscarinic receptors. Recent findings indicate that
ACh,
20 acting on muscarinic receptors, may contribute to the pathophysiology
and
pathogenesis of asthma and COPD.
Anticholinergic agents are believed to reverse the action of vagally derived
acetylcholine on airway smooth muscle contraction. Vagal tone is increased in
airway inflammation associated with asthma and COPD; this results from
25 exaggerated acetylcholine release and enhanced expression of downstream
signaling components in airway smooth muscle. Vagally derived acetylcholine
also
regulates mucus production in the airways. Anticholinergic drugs can
effectively
inhibit accelerated decline of lung function. Further, anticholinergic agents
can
achieve reductions in airway remodeling and lung function decline in addition
to
30 its effects as a bronchodilator (Reinoud et. al. "Review: Muscarinic
receptor
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41
signaling in the pathophysiology of asthma and COPD", Respiratory Research
2006, 7:73).
Thus, it is believed that though the therapeutic outcomes of these two
classes of drugs, the TRPA1 antagonists and the anticholinergic agent are
similar
to some extent, the mechanism of actions may vary to a good extent and thus
the
therapeutic effect of their combination in the treatment of respiratory
disorders is
highly unpredictable. Particularly, the therapeutic effect of the combination
of
TRPA1 antagonist and an anticholinergic agent is highly unpredictable.
The inventors of the present invention have surprisingly found that a
pharmaceutical composition comprising TRPA1 antagonist and an anticholinergic
agent are more effective in the treatment of respiratory disorders, and
provide
better therapeutic value when compared to both the actives alone (when
administered individually) for the treatment of respiratory disorders.
In an embodiment, the present invention relates to a method of treating a
respiratory disorder in a subject, said method comprising administering to the
subject the pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1
receptor activity of less than 1 micromolar and an anticholinergic agent. In
an
aspect of this embodiment, the TRPA1 antagonist has an IC50 for inhibiting
human
TRPA1 receptor activity of less than 1 micromolar having structure of
formulae:
(XII) or (D)
R9 R8 R7
0 S
R6 w
yN
R4 R5 NS
Het
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
group consisting of
0
o
R1,1\1_
I Ra R1õ,
R1 N , N
'1\1)Y1Ra \ I \ N ,0
Si N
0 N
I ,
R2 R2
5 5
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Rl, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
selected from the group comprising of hydrogen, halogen, cyano, hydroxyl,
nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
In a further embodiment, the present invention relates to a method of
treating a respiratory disorder in a subject, said method comprising
administering
the subject a pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1
receptor activity of less than 1 micromolar and an anticholinergic agent
selected
from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate
and
aclidinium or salts thereof
In a further embodiment, the present invention relates to use of
synergistically effective amount of a TRPA1 antagonist having an IC50 for
inhibiting human TRPA1 receptor activity of less than 1 micromolar and an
anticholinergic agent in the preparation of a pharmaceutical composition of
the
present invention for the treatment of a respiratory disorder in a subject. In
an
aspect of this embodiment, the TRPA1 antagonist has an IC50 for inhibiting
human
TRPA1 receptor activity of less than 1 micromolar having structure of
formulae:
(XII) or (D)
R9 R8 R7 Ali 0_,-----.....,0,
0 S\ 'W R6 0
SNH y H
H R4 R5 N'%s
Het H
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from
the
group consisting of
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0 , 0 , 0 ,
o
I \ Ra \ Ra I N p
0 N S
I I
R2 R2 1=1- 1=1-
Rl, R2 and Ra, which may be the same or different, are each independently
hydrogen or (Ci-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each
independently
selected from the group comprising of hydrogen, halogen, cyano, hydroxyl,
nitro,
amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl,
biaryl,
heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
In a further embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having an IC50 for inhibiting human TRPA1 receptor activity of less than 1
micromolar and an anticholinergic agent for the treatment of a respiratory
disorder
in a subject.
In an embodiment, the present invention relates to a method of treating a
respiratory disorder in a subject, said method comprising administering to the
subject the pharmaceutical composition comprising synergistically effective
amount of a TRPA1 antagonist having structure of formula:
0 \ F
0 (ANN
H3C.õ, F C F3
0 N -
0H 3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent is selected from a group consisting of tiotropium, oxitropium,
ipratropium,
glycopyrrolate and aclidinium or salts thereof
In an embodiment, the present invention relates to a method of treating
COPD by reducing neutrophil count in a subject, said method comprising
administering to the subject the pharmaceutical composition comprising
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
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0 S NN =
H3C.N Yi4:H F CF3
I
0 N S
aH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of this
embodiment, the respiratory disorder is asthma. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of reducing
neutrophil count in a subject, said method comprising administering to the
subject
the pharmaceutical composition comprising synergistically effective amount of
a
TRPA1 antagonist having structure of formula:
0 H s \
.N (ANN
H3C
2:)1
F CF3
0 N S
CH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating
asthma by inhibiting airway resistance in a subject, said method comprising
administering to the subject the pharmaceutical composition comprising
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
0S\
H3c.N H N N
FlICF3
0 N S
CH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
glycopyrrolate and aclidinium or salts thereof In another aspect of this
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embodiment, the respiratory disorder is asthma. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of inhibiting
airway resistance in a subject, said method comprising administering to the
subject
5 the pharmaceutical composition comprising synergistically effective
amount of a
TRPA1 antagonist having structure of formula:
0 s =
H3c.NYH F CF3
\
0 N S
aH3
and an anticholinergic agent. In an aspect of this embodiment, the
anticholinergic
agent selected from a group consisting of tiotropium, oxitropium, ipratropium,
10 glycopyrrolate and aclidinium or salts thereof In another aspect of the
embodiment, the composition is for inhalation administration.
In another embodiment, the present invention relates to use of
synergistically effective amount of a TRPA1 antagonist having structure of
formula:
0 s
H3c.NYcL,..HNN
F CF3
\
0 N s
15 aH3
and an anticholinergic agent in the preparation of a pharmaceutical
composition of
the present invention for the treatment of a respiratory disorder in a
subject. In an
aspect of this embodiment, the anticholinergic agent is selected from a group
consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and
aclidinium or
20 salts thereof
In a further embodiment, the present invention relates to a pharmaceutical
composition comprising synergistically effective amount of a TRPA1 antagonist
having structure of formula:
o 0 H s
H3c.N N N
F CF3
0 N S
al-13
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and an anticholinergic agent for the treatment of a respiratory disorder in a
subject.
The therapeutically effective amount of TRPA1 antagonist to be
administered per day ranges from about 10mcg/kg to about 20mg/kg, and
preferably from about 50mcg/kg to about 15mg/kg.
In one embodiment of the present invention the therapeutically effective
amount of tiotropium to be administered per day ranges from about 5mcg to
about
50mcg and preferably from about 10 mcg to about 36 mcg. Preferably, the
discrete
dosage strengths of tiotropium or its salt are 15 mcg or 18 mcg or 20 mcg or
22
mcg or 22.5 mcg or 25 mcg or 36 mcg.
In one embodiment of the present invention the therapeutically effective
amount of ipratropium to be administered per day ranges from about 10 mcg to
about 200 mcg and preferably from about 20 mcg to about 150 mcg. Preferably
the
discrete dosage strengths of ipratropium or its salt are 34 mcg or 42 mcg or
68 mcg
or 84 mcg or 102 mcg or 126 mcg or 146 mcg or 168 mcg.
In one embodiment of the present invention the therapeutically effective
amount of aclidinium bromide to be administered per day ranges from 150 mcg to
about 800 mcg, and preferably from about 200 mcg to about 600 mcg. Preferably
the discrete dosage strengths of aclidinium or its salt are 200 mcg or 400 mcg
or
600 mcg or 800 mcg.
The optimal dose of the active ingredient or the combination of the active
ingredients can vary as a function of the severity of disease, route of
administration, composition type, the patient body weight, the age and the
general
state of mind of the patient, and the response to behavior to the active
ingredient or
the combination of the active ingredients.
In the pharmaceutical composition as described herein, the active
ingredient may be in the form of a single dosage form (i.e., fixed-dose
formulation
in which both the active ingredients are present together) or they may be
divided
doses, formulated separately, each in its individual dosage forms but as part
of the
same therapeutic treatment, program or regimen, either once daily or
two/three/four times a day.
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Alternately, the invention relates to a pharmaceutical composition wherein
the composition is in the form of kit comprising separate formulations of
TRPA1
antagonist and the anticholinergic agent. The separate formulations are to be
administered by same or different routes, either separately, simultaneously,
or
sequentially, where the sequential administration is close in time or remote
in time.
For sequential administration, the period of time may be in the range from 10
min
to 12 hours.
Various animal models have been used for the evaluation of the therapeutic
efficacy of drug candidates for respiratory disorders like asthma and COPD.
For
example, commonly used strategy for evaluation of drug candidates in asthma is
the allergen sensitization and challenge method. The commonly used such model
is
the ovalbumin (OVA) sensitization and challenge in laboratory animals. Another
model that can be used is the methacholine challenge test by using invasive
whole
body plethysmograph.
A commonly used model for evaluation of drug candidates in COPD
involves the chronic exposure of the animal to SO2 or tobacco/cigarette smoke.
The model is believed to generate sloughing of epithelial cells, increase in
the
mucus secretions, increase in the polymorphonuclear cells and pulmonary
resistance, and increase in the airway hyper-responsiveness (in rats).
Another model that can be used for evaluation of drug candidates in COPD
involves the exposure of animals (e.g., rats) to lipopolysaccharide (LPS). The
exposure to LPS is believed to result in the influx of neutrophils in the
lungs, a
condition that is believed to be one of the characteristics of COPD.
It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be
construed as limiting, but merely as exemplifications of preferred
embodiments.
Other arrangements and methods may be implemented by those skilled in the art
without departing from the scope and spirit of this invention.
The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The
examples
should not be read as limiting the scope of the invention.
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EXAMPLES
EXAMPLE 1: Determination of ICso value of TRPA1 antagonists
The human ICso values were measured by the following method:
The inhibition of TRPA1 receptor activation was measured as inhibition of
allylisothiocyanate (AITC) induced cellular uptake of radioactive calcium.
Test compound solution was prepared in a suitable solvent.
Human TRPA1 expressing CHO cells were grown in suitable medium.
Cells were treated with test compounds followed by addition of AITC.
Cells were washed, lysed and the radioactivity in the lysate was measured
in Packard Top count after addition of liquid scintillant.
The concentration response curves for compounds were plotted as a % of
maximal response obtained in the absence of test antagonist, and the ICso
values
were calculated from such concentration response curve by nonlinear regression
analysis using GraphPad PRISM software.
Table 1: TRPA1 antagonists having a human ICso for inhibiting human TRPA1
receptor activity of less than 1 micromolar.
Compound No hTRPA1 ICso values Compound No hTRPA1 ICso values
1 920.9 nM 52 2.49 nM
2 381.8 nM 53 18.20 nM
3 73.35 nM 54 17.74 nM
4 98.32 nM 55 2.15 nM
5 66.28 nM 56 3.38 nM
6 97.42 nM 57 1.45 nM
7 47.37 nM 58 11.88 nM
8 55.02 nM 59 2.21 nM
9 102.5 nM 60 3.54 nM
10 46.74 nM 61 2.93 nM
11 46.27 nM 62 1.68 nM
12 51.68 nM 63 9.04 nM
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Compound No hTRPA1 ICso values Compound No hTRPA1 ICso values
13 48.21 nM 64 4.52 nM
14 60.42 nM 65 6.65 nM
15 53.57 nM 66 3.63 nM
16 58.94 nM 67 13.59 nM
17 56.02 nM 68 4.84 nM
18 13.38 nM 69 7.10 nM
19 26.13 nM 70 12.57 nM
20 20.09 nM 71 3.18 nM
21 48.18 nM 72 4.16 nM
22 79.77 nM 73 8.54 nM
23 43.93 nM 74 5.29 nM
24 138.1 nM 75 3.34 nM
25 58.55 nM 76 4.02 nM
26 47.91 nM 77 5.60 nM
27 65.45 nM 78 10.57 nM
28 6.49 nM 79 5.29 nM
29 11.38 nM 80 6.28 nM
30 34.03 nM 81 6.74 nM
31 17.3 nM 82 8.04 nM
32 5.96 nM 83 4.40 nM
33 5.37 nM 84 5.35 nM
34 38.46 nM 85 8.92 nM
35 18.05 nM 86 6.91 nM
36 49.92 nM 87 19.32 nM
37 12.26 nM 88 11.45 nM
38 15.92 nM 89 98.44 nM
39 26.56 nM 90 5.61 nM
40 22.82 nM 91 451.4 nM
41 11.04 nM 92 17.08 nM
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Compound No hTRPA1 ICso values Compound No hTRPA1 ICso values
42 11.38 nM 95 88.50 nM
43 18.37 nM 96 559.3 nM
44 8.36 nM 97 21.91 nM
45 26.39 nM 98 54.29 nM
46 41.31 nM 99 5.06 nM
47 33.61 nM 100 5.15 nM
48 18.12 nM 101 10.10 nM
49 3.98 nM 102 7.67 nM
50 16.73 nM 103 27.41 nM
51 4.84 nM 104 7.58 nM
EXAMPLE 2: Animal studies for the combination of Compound 52 and
tiotropium bromide.
The effect of Compound 52, tiotropium bromide and their combination on
5 methacholine challenge test in male Dunkin Hartley guinea pig was
evaluated
using invasive whole body plethysmograph (ElanTM RC, Buxco apparatus).
Animals and grouped as described in Table 2.
Table 2
Group Treatment Dose Route Number
Tiotropium of animals
Compound 52
bromide (N)
(mg/kg)
(mcg/kg)
1 Vehicle control- - - 9
Tiotropium
2 0.5 - i.v* 7
bromide
3 Compound 52- 10 i.p** 5
4 Combination 0.5 10 i.v*/i.p** 6
10 * intravenous; ** intraperitonial
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Animals were anesthetized by intraperitonial injection of urethane (lg/kg).
The surgical process carried out in the aseptic area. Right jugular vein of
anesthetized animal was exposed and cannulated with fine bore polythene tube.
Trachea was also cannulated for artificial respiration and to measure airway
resistance. The prepared animal was fixed in the invasive whole body
plethysmograph with artificial respiration (tidal volume -7 m1). Methacholine
challenge test was performed and the recordings were taken by the following
schedule.
= First log period: Baseline -5 min
= Second log period: Normal saline -3 min
= Third log period: Methacholine -3 min
This protocol was performed for all groups. Compound 52 (10mg/kg, i.p.)
was injected 4 hour prior to methacholine challenge. Tiotropium (0.5mcg/kg,
i.v)
was given at second log period. In third log period, the animal was injected
with
methacholine (60mcg/kg/2m1, i.v). The methacholine induced bronchoconstriction
(expressed as airway resistance (RI value in cmH20*sec/m1)) was recorded by
Buxco apparatus.
Table 3
% inhibition in airway
Mean airway resistance
Group Treatment resistance
(Mean SEM)
(Mean SEM)
1 Vehicle control 1.36 0.17 --
Tiotropium
2 1.51 0.32 -10.7 23.4
bromide
3 Compound 52 0.77 0.11 37.9 6.7
4 Combination 0.38 0.05 72.2 3.8*#
*p<0.05-treated groups vs Group 1; #p<0.01 vs Group 2
Combination of Compound 52 and tiotropium bromide was found to
produce significantly superior inhibition (synergistic effect) in airway
resistance
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compared to the individual and sum of the activity of both in methacholine
challenge as shown in Table 3 and Figure 1.
EXAMPLE 3: Animal studies for the combination of Compound 52 and
aclidinium bromide.
The effect of combination of Compound 52 and aclidinium bromide on
LPS induced neutrophilia in male SD rats was evaluated. Animals were grouped
as
mentioned in Table 4.
Table 4
Groups Treatment (n) Dose Exposure to
Aclidinium Compound 52
(mcg/ml, inh) (mg/kg, p.o.)
1 Saline control (6) - - saline
2 LPS control (8) - - LPS
3 Compound 52 (8) - 3
Aclidinium
4 50 -
bromide (8)
5 Combination (8) 50 3
*All groups were exposed to LPS (0111:B4) (100mcg/m1) for 40min except vehicle
control group
LPS was nebulized at concentration of 100 mcg m1-1 for 40 min at 0.4
ml/min and a pressure of 1.7 psig in a Perspex exposure chamber (1.5 x 1 x 1
ft)
fitted with nebulizer (RCI Hudson). Control animals were given saline exposure
under similar conditions. All the animals were treated with compounds as
mentioned in Table 4. Compound 52 (3mg/kg/5m1) was administered orally 2 h
prior to LPS and aclidinium (50mcg/m1) was nebulized at the rate of 0.05
ml/min
and exposed to the animals for 3 min prior LPS exposure.
Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure.
Animals were anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal
saline)
and BAL was done with PBS (3m1). This procedure was repeated three times and
the BAL fluid was pooled for the measurement of total leukocyte. Remaining BAL
fluid was centrifuged immediately at 4000 rpm for 20 min. The pellet formed in
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the bottom of the tube was used for the smear preparation for differential
leukocyte
count estimation. The smeared slides were fixed by alcohol and stained using
Leishman's stain further carried for differential leukocyte count.
Table 5
Dose No of neutrophils
Groups Treatment (n) Aclidinium Compound 52 (% inhibition;
(mcg/ml, inh) (mg/kg, p.o.) mean S.E.M.)
1 Saline (6) 0.02
0.01
2 LPS (8) 8.16
0.764
3 Compound 52 (8) 3
6.73 0.72 (20.4 7.7)
Aclidinium
4 50 7.13 1.03(21.1 7.2)
bromide (8)
Combination (8) 50 3 2.84 0.19 (65.4 2.3)@'""s
5 #p<0.001, saline vs LPS vehicle; @p< 0.001, LPS vehicle vs Combination;
'"p< 0.001, Aclidinium vs
Combination; $sp< 0.01, Compound 52 vs Combination; one-way ANOVA, Bonferroni
test.
Combination of compound 52 with aclidinium showed significant
inhibition in LPS induced neutrophilia compared to the individual treatments
(Table 5 and Figure 2). Compound 52 in combination with aclidinium showed
significant synergy in inhibition of neutrophilia in LPS model in SD rats.
EXAMPLE 4: Animal studies for the combination of Compound 52 and
tiotropium.
The effect of combination of Compound 52 and tiotropium on LPS induced
neutrophilia in female SD rats was evaluated. Female SD rats were grouped as
mentioned in Table 6. Compound 52 (3mg/kg/5m1) and tiotropium (1 mcg/ml as
inhalation for 3 min at the rate of 0.05 ml/min) were administered 2 and 1
hour
prior to LPS exposure respectively. LPS was nebulized at concentration of
100mcg
m1-1 for 40min at 0.4 ml min-1 and a pressure of 1.7 psig in a perspex
exposure
chamber (1.5 x 1 x 1 ft) fitted with nebulizer (RCI Hudson). Control animals
were
given saline exposure under similar conditions.
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Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure. Animal
was anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal saline) and BAL
was done with PBS (3m1). This procedure was repeated three times and the BAL
fluid was pooled for the measurement of total leukocyte. BAL fluid was
centrifuged immediately at 4000 rpm for 20 min and the pellet formed in the
bottom of the tube was used for the smear preparation for differential
leukocyte
count estimation.
Table 6
Dose
Groups Treatment (n) Tiotropium Compound 52 Exposure to
(mcg/ml, inh) (mg/kg, p.o.)
1 Saline (6) saline
2 LPS (8)
3 Compound 52 (8) 3
LPS
4 Tiotropium (8) 1
5 Combination (/0) 1 3
Combination of Compound 52 with tiotropium showed significant
inhibition in LPS induced neutrophilia compared to the individual treatments
(Table 7 and Figure 3). Compound 52 in combination with tiotropium showed
synergy in inhibition of neutrophilia in LPS model in SD rats.
Table 7
Dose No of
neutrophils
Groups Treatment (n) Tiotropium Compound 52 (% inhibition
(mcg/ml, inh) (mg/kg, p.o.) mean S.E.M.)
1 Saline (6) 0.0 0.0
2 LPS (8) 7.9 0.74
3 Compound 52 (8) 3 6.7
0.9 (17.9 7.6)
4 Tiotropium (8) 1 6.8 0.7(18.9
5.6)
5 Combination (/0) 1 3 3.0 0.4 (62.4 5.5)
#p<0.001, saline vs LPS vehicle; @p< 0.001, LPS vehicle vs Combi; **p< 0.01,
Tiotropium vs Combi; ssp<
0.01, Compound 52 vs Combi; one-way ANOVA, Bonferroni test.
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EXAMPLE 5: Animal studies for the combination of TRPA1 antagonist and
ipratropium bromide.
The effect of Compound 52 and ipratropium bromide on LPS induced
neutrophilia in male SD rats was evaluated. Animals were grouped as mentioned
in
5 Table 8.
Table 8
Dose
Groups Treatment (n) Ipratropium Compound 52 Exposure to
(mg/ml, inh) (mg/kg, p.o.)
1 Saline (7) - Saline
2 LPS (5) -
3 Compound 52 (6) - 6
Ipratropium 1 LPS
4
bromide(6)
5 Combination (6) 1 6
LPS at a concentration of 100mcg m1-1 was nebulized for 40 min at 0.4
ml/min and a pressure of 1.7 psig in a Perspex exposure chamber (1.5 x 1 x 1
ft)
All the animals were treated as mentioned in Table 8. Compound 52
(6mg/kg/5m1) and ipratropium bromide (1 mg/ml as inhalation for 10 min at the
rate of 0.3 ml/min) were administered 2 and 0 hour prior to LPS exposure
15 respectively.
Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure.
Animals were anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal
saline)
and BAL was done with PBS (3m1). This procedure was repeated three times and
the BAL fluid was pooled for the measurement of total leukocyte.
20 Remaining BAL fluid was centrifuged at 4000 rpm for 20 min. The pellet
formed in the bottom of the tube was used for the smear preparation for
differential
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leukocyte count estimation. The differential leukocyte count was done using
Leishman's stain.
The total number of neutrophils in each BAL sample was calculated using the
formula:
Total cell count X 105/mL X % neutrophils
Total No. of neutrophils (in BAL) = ----------------------------
100
% inhibition of neutrophils was calculated using the following formula:
Avg. neutrophils (LPS control) - neutrophils (treatment)
% Inhibition of neutrophils ¨ ---------------------------------- X 100
Avg. neutrophils (LPS control) - Avg. neutrophils (Saline control)
Statistical analysis was performed using One Way ANOVA followed by
Dunnett's multiple comparisons with the help of Graph Pad Prism software.
Statistical significance was set at p<0.05.
Results:
Combination of compound 52 with ipratropium showed significant inhibition in
LPS induced neutrophilia compared to the respective individual treatments
(Table
9 and Fig. 4). Compound 52 in combination with ipratropium showed significant
synergy in inhibition of neurophilia in LPS model in SD rats.
Table 9
Dose No of neutrophils
Groups Treatment (n) Ipratropium Compound 52 (% inhibition;
(mg/ml, inh) (mg/kg, p.o.) mean S.E.M.)
1 Saline (6)
0.02 0.02
2 LPS (5)
8.1 1.4#
3 Compound 52 (6) 6
8.4 O.8(-3.2 10.0)
4 Ipratropium (6) 1 6.2 0.6 (23.0
7.6)
5 Combination (6) 1 6 2.8 0.3 (66.1 3.9)
@'**'$$$
#p<0.001, saline vs LPS vehicle; @p< 0.001, LPS vehicle vsCombi; *p< 0.05,
Ipratropium vs Combi; $$$p<
0.001, Compound 52 vs Combi; one-way ANOVA, Dunnett's multiple comparison
test.
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Although the invention herein has been described with reference to
particular embodiments, it is to be understood that these embodiments are
merely
illustrative of the principles and application of the present invention. It is
therefore
to be understood that numerous modifications may be made to the illustrative
embodiments of the present invention as described.
All publications, patents, and patent applications cited in this application
are herein incorporated by reference to the same extent as if each individual
publication, patent, or patent application was specifically and individually
indicated to be incorporated herein by reference.
